An experimental biologic drug for osteoporosis increased bone density and reduced fractures in men and women in two controlled clinical trials.

Three years of treatment with denosumab reduced radiographic spine fractures more than two-thirds in the randomized FREEDOM study of nearly 7,900 postmenopausal women.

Overall, those fractures appeared in 2.3 percent of the denosumab group, compared with 7.2 percent of patients taking placebo, according to Dr. Steven Cummings of California Pacific Medical Center in San Francisco and colleagues.

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And a separate trial by Dr. Matthew Smith of Massachusetts General Hospital in Boston and colleagues documented a similar reduction in new vertebral fractures after two years of denosumab in 1,468 men undergoing androgen-deprivation therapy for prostate cancer, and hence at risk for bone loss.

Both studies were published online in the New England Journal of Medicine. Both sets of researchers reported increases in bone mineral density (BMD) at various body sites with denosumab, whereas no change or decreases in BMD were seen in the placebo groups.

Preliminary results from the two studies were reported last year.

Sundeep Khosla, MD, of the Mayo Clinic in Rochester, Minn., in an accompanying NEJM editorial.Although the drug did not seem to increase infection rates in either study, Khosla noted that its potential to depress immune function remained an issue.

He added that its cost could "considerably limit its use" if it turns out to be much higher than zoledronic acid (Reclast), the bisphosphonate drug that appears to be denosumab's most direct competitor.

The double-blind, randomized, placebo-controlled study by Cummings and colleagues enrolled 7,868 women 60 to 90 years old with established osteoporosis.

Patients received calcium supplements of at least 1,000 mg/day. Vitamin D supplements were provided as well. No bisphosphonates or other osteoporosis drugs were allowed.

Denosumab was given as an injection every six months for three years. Lateral spine radiographs were taken annually and analyzed at a central facility for new vertebral fractures.

New Drug Appears to Cut Fracture Risk in Men, Women

At the three-year evaluation, the researchers found that the risk for new vertebral fractures detected by imaging in the group taking denosumab are only about one-third of that in those taking placebo. Similar reductions were seen in rates of vertebral fracture cases seen by doctors and the number of cases involving two or more vertebral fractures detected by X-ray. The group receiving denosumab also enjoyed better improved density.

In the other study, involving men with prostate cancer undergoing anti-androgen therapy, the basic pattern of results was similar. As in the FREEDOM trial, the drug was given every six months by injection.

Smith and colleagues found the overall incidence of new vertebral fractures in the study after three years of treatment was 1.5 percent with denosumab versus 3.9 percent among placebo patients.

Adverse effects were largely similar between treatment groups in both studies, though the male patients showed slightly higher rates (34.6 percent versus 30.6 percent for serious events and 5.9 percent versus 4.6 percent for serious events related to infections). But notably absent from the list of adverse events was osteonecrosis of the jaw, a rare but worrisome side effect of bisphosphonate drugs.

Although the data do not rule out the possibility that osteonecrosis could occur with denosumab, it was encouraging to see no cases thus far, Cummings suggested. He said follow-up of FREEDOM participants would continue for 10 years, which may provide a more definitive view of the risk.

Denosumab's manufacturer, Amgen, has not yet announced the pricing for the drug. Nevertheless, as a biologic drug, denosumab is widely expected to be relatively expensive.

But another academic specialist contacted by MedPage Today and ABC News suggested a higher price could be acceptable given denosumab's potential advantages.

Endocrinologist Dr. Roberto Pacifici of Emory University in Atlanta said the "number needed to treat" in preventing fractures has been low in the denosumab studies reported to date.

The Question of Cost

"Therefore the cost of the drug is likely to be [worthwhile] in many patients," he said. "Guidelines will have to be developed in order to use this agent in the most cost-effective way."

Cummings said that if the drug is approved, he would consider it primarily for patients with a poor history on bisphosphonates.

"Those who have had trouble with oral drugs," because of side effects or compliance problems, would be the main candidates for denosumab, he said.

Another point in denosumab's favor, Cummings said, is that it is less persistent in bone than many bisphosphonates, making its activity potentially reversible — an important point for patients experiencing adverse effects.

In addition, Dr. Khosla pointed out, "since bisphosphonates are cleared by the kidney and contraindicated in patients with renal insufficiency, denosumab (which is cleared by nonrenal metabolism) may prove to be a safe drug in these patients, although studies that directly address this issue need to be done."

Amgen filed last December for FDA approval of the agent for treatment and prevention of postmenopausal osteoporosis in women and treatment and prevention of bone loss in patients undergoing hormone ablation therapy for either prostate or breast cancer. The two trials were funded by Amgen.